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Contrast agents

Contrast agents description/claims

The present invention relates to particles susceptible for uptake by macrophages and/or Kupffer cells and to pharmaceuticals containing such particles. The particles comprise coated cores of the metallic element of tungsten or of tungsten in mixture with other metallic elements wherein the average diameter of said particle is greater than 20 nm. The invention also relates to the use of such pharmaceuticals as contrast agents in diagnostic imaging, in particular in X-ray imaging of atherosclerotic plaque and liver tumors, and to contrast media containing such cores of the metallic element of tungsten or tungsten in mixture with other metallic elements

All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast, the smaller the body structures that may be visualized in the imaging procedures. I.e. increased contrast can lead to increased spatial resolution and thereby achieving a safer detection of the target for the diagnostic procedure.

The diagnostic quality of images is, for a given spatial resolution, strongly dependent on the inherent noise level in the imaging procedure, and the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images. The ratio of the signal level and the noice level is usually denoted signal to noise ratio, abbreviated SNR.

Achieving improvement of the diagnostic quality factor has long been and still remains an important goal. In techniques such as X-ray, magnetic resonance imaging (MRI) and ultrasound, one approach to improve the diagnostic quality factor has been to introduce contrast enhancing materials, contrast agents, into the body region to be imaged.

Thus in X-ray for example early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. More recently the field of X-ray contrast agents has been dominated by soluble iodine containing compounds and specifically iodinated aryl compounds such as those marketed by Amersham Health AS under the trade names Omnipaque™ and Visipaque™.

Work on X-ray contrast agents having heavy metals as the contrast enhancing element has to a great extent concentrated on aminopolycarboxylic acid (APCA) chelates of heavy metal ions. Recognising that effective imaging of many body sites requires localization at the body sites in question of relatively high concentrations of the metal ions, there have been suggestions that polychelants, that is substances possessing more than one separate chelant moiety, might be used to achieve this. Further work has been concentrated on the use of multinuclear complexes that are complexes wherein the complexed moiety itself comprises two or more contrast enhancing atoms, see Yu, S. B. and Watson, A. D. in Chem. Rev. 1999, 2353-2377. Thus, for X-ray or ultrasound the complexes would comprise two or more heavy metal atoms and for MRI the complex would contain two or more metal atoms with paramagnetic properties. Yu, S. B. and Watson, A. D. also discuss use of metal-based X-ray contrast media. Tungsten powder is noted for use as an X-ray contrast additive in embolic agents used in the treatment and preoperative embolisation of hypervascular tumors. However, they find it likely that general intravascular use of heavy metal complexes is limited by safety concerns and dosage requirements.

X-ray contrast agents for parenteral administration are mainly hydrophilic of nature and have approximately the same extracellular biodistribution and are preferably renally excreted. Various attempts are made to achieve organ specific X-ray contrast agents that accumulate in organs and cells of the body and which can be administered parenterally. Iodinated aryl based X-ray contrast agent for example has been linked to macromolecular substrates such as starch in order to improve their vascular half-life. Potential liver contrast agents based on biodegradable particles are proposed in e.g. WO-A-8900988 and WO 9007491. Liposomes containing ionic or non-ionic iodinated aryl compounds have also been suggested, see e.g. WO-A-8809165 and U.S. Pat. No. 5,676,928. In the later years targeting moieties such as specific vectors binding to receptors at the target organs or cells have been proposed.

PCT/NO2004/00036 proposes particles with a core of the metallic element tungsten optionally together with other metallic elements and being coated with a coating layer. The particles should preferable be below the kidney threshold of about 6 to 7 nm to ensure excretion through the kidneys. The coating could be monomeric and polymeric and provide particles with a short half-life in vivo. Surface coatings with targeting moieties embedded, such as antibodies, are also proposed for the targeting of various body organs and structures, including tumours and macrophages.

Cardiology and oncology are important medical areas where there is a continuing need for reliable diagnosis of diseases and for monitoring the treatment of diseases.

Cardiovascular disease (CVD) is the leading course of death in the Western world and encompasses dysfunctional conditions of the heart, arteries, veins and lungs; which supply oxygen to vital life-sustaining areas of the body like the brain, the heart itself, and other vital organs. These conditions include coronary heart disease (CHD), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), atherosclerosis, and thrombosis, and can lead to potentially life-threatening events as myocardial infarction (Ml), pulmonary embolism (PE) and stroke. One factor in common for all these diseases is the involvement of macrophages.

CHD is the most prevalent of the cardiovascular diseases. In 1998 it was estimated that CHD was the cause of 7 million deaths worldwide. CAD precedes CHD, and in the majority of cases the underlying cause is atherosclerosis. Atherosclerosis can be a benign disease for decades until the atherosclerotic plaque becomes atheromatous and potentially symptom producing. The plaque can obstruct blood flow resulting in stenosis of the artery, leading to acute myocardial ischemia in the case of coronary arteries. Additionally, mature atherosclerotic plaques can rupture resulting in the exposure of thrombogenic lipid, and these plaque components can form a trombous which completely blocks the artery. Angina is a common manifestation of CHD and is often the forerunner to more serious complications such as acute coronary syndromes including unstable angina, myocardial infarction and sudden cardiac death. Plaque rupture precedes the majority of clinical events and the vulnerability of plaque is the most important predictor of clinical outcome.

In cardiology, safe and early diagnosis of plaque and in particular of atherosclerotic plaque is therefore of great importance. Early diagnosis dramatically improves the outcome of the treatment of such diseases. It is well known that atherosclerotic plaques are infiltrated with a relatively large fraction of macrophages. The more vulnerable the plaque is the higher is the amount of macrophages in the plaque. A histological definition of “vulnerable plaque” is a plaque with a fibrous cap thinner than 65 μm and with a content of more that 25 cells in a 3.3 mm microscopic field which would correspond to an amount of about 4% macrophages in the fibrous cap, see “Handbook in vulnerable plaque”, Martin Dunitz; N.Y. Eds. R. Waksman and P. W. Serruys, pp 39-41. Macrophages are usually of a size between 8 and 30 μm. Macrophages will recognise and take up particles by phagocytosis from the blood pool. Macrophages can hence be used as a tool to concentrate or target contrast agents to specific macrophage containing organs or structures in the body.

In oncology, liver tumours such as hepatomas and metastatic spread to the liver are major causes of death in the world. There is a continuing need for methods and products to help in the early diagnosis of cancer. Cancer tissues in general have different vascularity from healthy tissues and may be detected as an area of modified contrast. However, X-ray examination of the liver will typically require high amounts of iodinated contrast agent and injection of contrast agent containing ca. 9 g iodine will be required, see WO-A-8809165. The Kupffer cells reside in the liver and will take up and initially break down particles in a similar fashion as the macrophages. Kupffer cells are not present or only present to a low extent in liver tumour tissue. Hence there is a possibility to identify cancerous liver tissue as tissue that give no or very low signal in X-ray examination of the liver after administration of a suitable X-ray contrast agent.

None of the attempts to provide specific X-ray contrast agents for imaging of atherosclerotic plaque and/or liver tumours has resulted in commercial products. Problems encountered in this regard has been insufficient contrast in the target organ or structure and the need for very high doses of contrast agents e.g. in the form of X-ray contrast agents enclosed in liposomes which may lead to adverse reactions. It has hence been difficult to achieve a satisfactory signal to noise ratio (SNR) sufficient to secure a safe and accurate diagnosis in particular of small lesions.

It has now surprisingly been found that compounds being susceptible for uptake by macrophages and/or Kupffer cells can be provided that provide sufficient contrast in X-ray contrast examination of the vascular bed and for the identification of tumour tissue. Such compounds are particles comprising a core of the metallic element tungsten optionally together with other metallic elements and being coated with a coating layer wherein the average diameter of said particle is greater than 20 nm.

The invention will now be described in further details. The various embodiments are also specified in the attached claims and form part of the entire description of the invention.

Coated nanoparticles comprising tungsten are enclosed in PCT/NO2004/00036, which is hereby incorporated by reference. The particles of this document are however small to facilitate fast excretion; preferably their size is below the kidney threshold of 6 to 7 nm to secure secretion through the kidneys.

According to the present invention it has been found that in order to achieve sufficient uptake by the macrophages and/or Kupffer cells and to achieve sufficient contrast and SNR, it is necessary to provide particles of larger sizes than previously suggested, in particular particles with an average diameter of at least 20 nm.

It should be noted that the terms core, metallic core and tungsten core are used interchangeably in the further document. By the expression pharmaceuticals is also enclosed the particles which constitute the active principle of the pharmaceutical. Further embodiments are specified in the attached claims and will be outlined in the text.

The compounds of the invention are particles comprising a core and a coating layer. The particle size can vary in range but should be at least 20 nm, e.g. from 20 to 1000 nm and preferably from 20 to 200 nm. Even more preferably the particle size should be from about 100 to 200 nm. The particle size should therefore preferably be above the kidney threshold of about 6 to 7 nm (Kobayashi, H.; Brechbiel, M. W. Molecular Imaging 2, 1 (2003)).

Metallic tungsten has a relatively high X-ray attenuation value, a low toxicity and is available at an acceptable price.

The core of the particle contains tungsten in its metallic form or tungsten in mixture with other suitable metallic elements. Preferably the tungsten content is between 20 and 100 weight %, more preferably between 50 and 100 weight %, and even more preferably of 85 to 100 weight % and particularly preferably between 95 and 100 weight %. Cores of about 100% tungsten are generally preferred.

Introducing other metallic elements in the tungsten core can provide improved properties to the core e.g., can improve the stability, monodispersity, the synthesis and/or the rate of formation of the metal core. Preferably 5 to 15 weight % of rhenium, iridium, niobium, tantalum or molybdenum either as a single element or as mixtures of elements are feasible additives, most preferred are rhenium and iridium. All these elements are miscible with tungsten and small amounts of rhenium and/or iridium improve the low temperature plasticity of the metallic core.

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